ROLE OF HSP 110 IN TAUOPATHY

HSP 110 在 Tauopathy 中的作用

• 批准号: 8394589
• 负责人: NAHID F MIVECHI
• 金额: --
• 依托单位: CHARLIE NORWOOD VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394589
• 关键词: Acute Brain Injuries; Age; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Appearance; Applications Grants; Axon; Behavioral; Brain; Brain Injuries; Caring; Cause of Death; Cells; Cerebrospinal Fluid; Cessation of life; Clinical; Cognitive; Complex; Development; Disease; Down Syndrome; Event; Exhibits; Exposure to; Family member; Future; Generations; Goals; Heat shock proteins; Impaired cognition; In Vitro; Inherited; Injury; Isomerase; Knowledge; Life; Location; Microtubule-Associated Proteins; Microtubules; Molecular; Molecular Chaperones; Molecular Machines; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Organism; Pathology; Patients; Pattern; Pick Disease of the Brain; Play; Production; Protein Dephosphorylation; Proteins; Records; Recovery; Risk; Role; Senile Plaques; Social Problems; Tauopathies; Testing; Tg2576; Therapeutic; Toxic effect; Traumatic Brain Injury; Variant; Veterans; Wild Type Mouse; age related; amyloid precursor protein processing; brain tissue; combat; corticobasal degeneration; disability; hyperphosphorylated tau; in vivo; mouse model; mutant; pre-clinical; prevent; protein degradation; protein misfolding; response; tau Proteins; tau aggregation

Potential Impact on Veteran's Heath care is that traumatic brain injury (TBI), which is the main cause of death and disability in people under 35 and a common occurrence in combat situations, leads to significant deficiency in cognitive and social problems and significant amyloid beta (A¿) generation. Furthermore, there is evidence of increased amyloid deposition and an increased risk of development of Alzheimer's disease (AD) following TBI. However, our knowledge regarding the treatment of AD is still incomplete. The neuropathological hallmarks of AD and other tauopathies include accumulation of senile plaques and/or neurofibrillary tangles (NFTs) that causes neurons to degenerate. Clinical records suggest that tau, which is localized in axons, plays a pivotal role in neurodegenerative disorders that are related to protein malfunction. Heat shock proteins (Hsps) such as Hsp110 and Hsp70i are highly expressed following exposure to environmental insults. Their role in neuronal disorders is supported by studies showing that several Hsps are components of NFTs. As such, Hsps have been detected in NFTs containing tau, in neuritic plaques of AD brain, and in the brain tissue following TBI. A direct indication of the role of Hsps in neurodegenerative disease is provided by our discovery that hsp110-/- mice exhibit an age-dependent accumulation of hyperphosphorylated tau (p-tau) and neurodegeneration. We have also found that Hsp110, tau, and Pin1 isomerase, whose deletion in mice leads to tauopathy are in the same complexes. Since the Hsp110 family member, Hsp70 has been shown to be involved in amyloid precursor protein (APP) processing in cells, we tested if hsp110-/- mice crossed with mice expressing a mutant APP (Tg2576+) exhibit accelerated pathology in vivo. Results indicate that indeed hsp110- /-Tg2576+ mice exhibit neuritic plaques at a younger age than the hsp110+/+Tg2576+ mice strongly suggesting a role for Hsp110 (and Hsp70i) in AD pathology in vivo. Therefore, understanding the mechanisms by which Hsp110 and Hsp70i prevent p-tau accumulation, reduce AD pathology, and impact TBI are the subject of this grant application. We hypothesize that Hsp110 and Hsp70i are critical for proper dephosphorylation of tau and are protective during AD and following TBI, and prevent neuronal death. In our proposed studies, we will determine the expression and intra-axonal localization of Hsp110, Hsp70i, tau, or if Hsp110 and Hsp70i are substrates of Pin1. As an example of neurodegenerative diseases associated with tauopathy, we will use hsp110-/-Tg2576+ mice to establish the role of Hsp110 complexes in APP processing and A¿ production in vivo; since the expression of Hsps increases following environmental insults and because TBI is known to increase the risk for developing AD, we will investigate if the presence of Hsp110 and Hsp70i play a role in the recovery from TBI, and if transiently increasing the levels of Hsps accelerate recovery following TBI; we will also examine the brain tissue sections from healthy or AD patients to determine the locations of Hsp110, Hsp70i in senile plaques; Finally, we will use cerebral spinal fluid (CSF) from the patients who have received TBI to determine whether the levels of Hsp110 or Hsp70i following injury correlates with the extent of brain injury.

创伤性脑损伤（traumatic brain injury，TBI）是退伍军人死亡的主要原因，对退伍军人的健康护理有潜在的影响 35岁以下的人和残疾以及在战斗情况下的常见情况， 在认知和社会问题和显着的淀粉样蛋白β（A？）的产生。此外，有证据表明， 淀粉样蛋白沉积增加和阿尔茨海默病（AD）发展风险增加， 创伤性脑损伤然而，我们对AD治疗的认识仍然不完整。神经病理 AD和其它tau蛋白病的标志包括老年斑和/或神经纤维缠结的积累 （NFT）导致神经元退化。临床记录表明，位于轴突中的tau蛋白， 在与蛋白质功能障碍有关的神经退行性疾病中起关键作用。热休克蛋白 热休克蛋白（Hsps）如Hsp 110和Hsp 70 i在暴露于环境损伤后高度表达。他们的 在神经元疾病中的作用得到了研究的支持，研究表明几种Hsp是NFT的组分。作为 因此，在含有tau的NFT中、在AD脑的神经炎斑中和在脑组织中检测到Hsps TBI之后。我们的发现为热休克蛋白在神经退行性疾病中的作用提供了直接的证据 hsp 110-/-小鼠表现出年龄依赖性过度磷酸化tau（p-tau）积累， 神经变性我们还发现Hsp 110、tau蛋白和Pin 1异构酶，它们在小鼠中的缺失导致 与tau蛋白病的关系是相同的自Hsp 110家族成员以来，Hsp 70已被证明是 参与细胞中淀粉样前体蛋白（APP）的加工，我们测试了hsp 110-/-小鼠是否与小鼠杂交， 表达突变APP（Tg 2576+）的小鼠在体内表现出加速的病理学。结果表明，hsp 110- /-Tg 2576+小鼠在比hsp 110 +/+ Tg 2576+小鼠更年轻的年龄表现出神经炎斑块，这强烈表明了Hsp 110 +/+ Tg 2576+小鼠的神经炎性斑块。 Hsp 110（和Hsp 70 i）在体内AD病理学中的作用。因此，了解这些机制， Hsp 110和Hsp 70 i防止p-tau积累，减少AD病理，并影响TBI是本发明的主题。 补助金申请我们假设Hsp 110和Hsp 70 i对tau蛋白的适当去磷酸化至关重要， 在AD期间和TBI后具有保护作用，并防止神经元死亡。在我们的研究中，我们将 确定Hsp 110、Hsp 70 i、tau的表达和轴突内定位，或者Hsp 110和Hsp 70 i是否 Pin 1的底物。作为与tau蛋白病相关的神经退行性疾病的例子，我们将使用 hsp 110-/-Tg 2576+小鼠，以确定Hsp 110复合物在体内APP加工和A？产生中的作用; 由于环境损伤后Hsps的表达增加，并且已知TBI会增加， 发展为AD的风险，我们将调查Hsp 110和Hsp 70 i的存在是否在恢复中发挥作用。 如果短暂增加Hsps水平加速TBI后的恢复，我们还将 检查来自健康或AD患者的脑组织切片，以确定Hsp 110、Hsp 70 i在 老年斑;最后，我们将使用接受TBI患者的脑脊液（CSF）， 确定损伤后Hsp 110或Hsp 70 i的水平是否与脑损伤的程度相关。